During the current period we have demonstrated that women who avoid dealing with the stress of infertility fare less well than those who don't. The one year prospective study enrolled 102 women with primary ovarian insufficiency, a distinct type of infertility. Women with this condition stop having regular menstrual periods before age 40 and develop symptoms normally associated with menopause, such as hot flashes and vaginal dryness. Most women with this condition are never able to conceive a child. At the outset of the study we asked women to report on a variety of factors: 1) uncertainty about their diagnosis, 2) stigma, 3) optimism, 4) self-esteem, 5) emotional wellbeing, 6) emotional distress, and 7) coping methods. Women who were 1) less uncertain about the diagnosis, 2) less stigmatized by the diagnosis, and 3) less prone to feel negative emotions at the beginning of the year showed less emotional distress at the end of the year. A key reason these women fared better was that they were less likely to avoid dealing with the emotional stress of their diagnosis. Our findings support a conclusion to mark several critical factors helping to reduce emotional distress among women with primary ovarian insufficiency. These include: 1) the provision of clear/accurate information about the condition, 2) efforts to help reduce feelings of stigma, and 3) support and encouragement to confront rather than to avoid the stresses associated with infertility. In another study we completed during this period we investigated autoimmune aspects of primary ovarian insufficiency. Some women develop primary ovarian insufficiency caused by abnormal function of a gene important for regulating normal function of the immune system. Autoimmune poly-endocrine syndrome type 1 (APS1) is a monogenic disorder that features multiple autoimmune disease manifestations. It is caused by mutations in the Autoimmune regulator (AIRE) gene, which promotes thymic display of thousands of peripheral tissue antigens in a process critical for establishing central immune tolerance. We worked as part of an international team and used proteome arrays to perform a comprehensive study of autoimmune targets in APS1. Interrogation of established autoantigens revealed highly reliable detection of autoantibodies, and by exploring the full panel of more than 9000 proteins we further identified MAGEB2 and PDILT as novel major autoantigens in APS1. Our proteome-wide assessment revealed a marked enrichment for tissue-specific immune targets, mirroring AIRE's selectiveness for this category of genes. Our findings also suggest that only a very limited portion of the proteome becomes targeted by the immune system in APS1, which contrasts the broad defect of thymic presentation associated with AIRE-deficiency and raises novel questions what other factors are needed for break of tolerance. During the current period we are also analyzing genomic sequencing data on women with primary ovarian insufficiency. The goal is to uncover new mechanisms to explain why the disorder occurs. Presently in 90% of cases no cause can be identified. The requisite data sharing agreements are in place. We have obtained approval from our ethics review board to enter de-identified data into a centralized system which will form the basis for collaborative research. We also have approval to inform participants of important genetic clinical findings which are not directly related to the research questions. There are major gaps in knowledge regarding the etiologic mechanisms, psychosocial effects, natural history, and medical and psychosocial management of women with disorders of the hypothalamic-pituitary-ovarian axis. An international research consortium and disease registry formed under the guidance of an umbrella organization would provide a pathway to comprehensively increase basic and clinical knowledge about these conditions. Such a consortium and patient registry also would provide clinical samples and clinical data with a goal toward defining the specific pathogenic mechanisms. An international collaborative approach that combines the structure of a patient registry with the principles of integrative care and community-based participatory research is needed to advance the field of primary ovarian insufficiency. The program is in the early phases of organizing such an international effort using primary ovarian insufficiency as the focus.